Skin lightening compositions

ABSTRACT

The present invention relates to a skin lightening composition comprising 
     (a) a safe and effective amount of a compound of the formula (I) ##STR1##  wherein Z is Oxygen or Sulfur, (b) an average polarity solvent 
     (c) a polyhydric alcohol 
     (d) a solid fatty alcohol 
     (e) a nonionic surfactant 
     (f) water, and 
     (g) lecithin 
     wherein at least a portion of the above components (a), (b), (c), (d), (e), (f) and (g) forms a liquid crystal.

TECHNICAL FIELD

The present invention relates to the field of skin lightening.Specifically, the present invention relates to novel compositionscomprising a liquid crystal which enhance skin penetration effect ofspecific hydroquinone derivatives for skin lightening.

BACKGROUND OF THE INVENTION

The specific hydroquinone as shown in formula (I) is known as a skinlightening compound. See WO9523780. ##STR2## wherein Z is oxygen orsulfur.

The combination of the specific hydroquinone derivatives and penetrationenhancers is disclosed in WO9523780.

WO9523780 describes that penetration enhancers are disclosed in Mahjour,M., B. Mauser, Z. Rashidbaigi & M. B. Fawzi, "Effect of Egg YolkLecithins and Commercial Soybean Lecithins on In Vitro Skin Permeationof Drugs", Journal of Controlled Release, Vol. 14 (1990), pp. 243-252.The journal discloses Lecithin as a penetration enhancer. However, thereis no description of a liquid crystal comprising specific hydroquinonederivatives and lecithin which have penetration enhancing effect.

It is an object of the present invention to provide compositions forlightening mammalian skin which has a good penetration effect, so thatthe specific hydroquinone derivatives which are skin lightening activescan penetrate effectively and work effectively.

SUMMARY OF THE INVENTION

The present invention relates to a skin lightening compositioncomprising

(a) a safe and effective amount of a compound of formula (I) ##STR3##wherein Z is oxygen or sulfur. (b) an average polarity solvent

(c) a polyhydric alcohol

(d) a solid fatty alcohol

(e) a nonionic surfactant

(f) water, and

(g) lecithin

wherein at least a portion of the above components (a), (b), (c), (d),(e), (f) and (g) forms a liquid crystal.

DETAILED DESCRIPTION OF THE INVENTION

The compound of the formula(I) have a good skin lightening effect inmammals, however it is expected to strengthen the penetration effect ofthe compound of formula (I) to mammal's skin. It has been unexpectedlyfound that the subject composition achieve good penetration in mammals'skin of the compounds of formula (I).

As used herein, "topical application" means directly laying on orspreading on outer skin.

As used herein, "skin lightening" means decreasing melanin in skin,including one or more of overall lightening of basal skin tone,lightening of hyperpigmented lesions including age spots, melasma,chloasma, freckles, post inflammatory hyperpigmentation or sun-inducedpigmented blemishes.

As used herein, "solid" means solid form at the temperature of 25° C.,and "liquid" means liquid form at the temperature of 25° C.

As used herein, all percentages are by weight unless otherwisespecified.

The typical examples of the compound of fonnula(I) is as follows.

4-[(tetrahydro-2H-pyran-2-yl)oxy]phenol (hereinafter called THPOP).

4-[(tetrahydro-2H-thiopyan-2-yl)oxy]phenol.

These compounds are produced by the method described in WO9523780.

A skin lightening composition of the present invention comprisespreferably from about 0.001% to about 10%, more preferably from about0.01% to about 80/%, still more preferably from about 0.1% to about 5%,most preferably from about 0.5% to about 3% of the compound of theformula(I) as an active agent in a topical composition.

Use of subject compositions comprising over 3% of an active is preferredfor lightening of hyperpigmented lesions and other areas wheresubstantial lightening is desired.

Average Polarity Solvent

In order to dissolve the compounds of formula(I), since the compounds offormula(I) are molecules of average polarity being neither soluble invery polar solvents nor very non polar solvents, it is necessary to bedissolved in an average polarity solvent. The average polarity solventscould preferably be solvents which have the ratio of Organicity andInorganicity (Organicity/Inorganicity) of 0.2 to 3.6, more preferably besolvents which have the ratio of Organicity and Inorganicity(Organicity/Inorganicity) of 0.5 to 3.5. The ratio of Organicity andInorganicity (Organicity/Inorganicity) is described in PharmaceuticalBulletin Vol. 2, No. 2, 163 (1954); and The Field of Chemical (Kagaku noRyoiki) Vol. 11, No. 10, October 1957. The average polarity solventsinclude liquid triglycerides such as castor oil, olive oil, andcapric/caprylic triglyceride; cosmetically acceptable ester oil such asisopropyl palmitate, oleyl oleate, 2-octyidodecyl myristate andneopentyl glycol dioctoanate (trade name: Cosmol 525 manufactured byNisshin oil Mills LTD.); liquid fatty alcohols such as oleyl alcohol,isostearyl alcohol, lanolin alcohol, hexadecyl alcohol, octyidodecanolalcohol, linoleyl alcohol, linolenyl alcohol, arachidyl alcohol and2-octyl dodecanol; liquid fatty acids such as oleic acid and isostearicacid; octyl methoxy cinnamate; cinoxate; and 2-ethylphexylp-dimethyaninobenzoate. The following nonionic surfactants can be usedas the average polarity solvents. Even if the following nonionicsurfactants are used as the average polarity solvents, the othernonionic surfactants mentioned later (the "Nonionic surfactant"explanation part in this specification) are necessary for the presentinvention. Nonionic surfactants as the average polarity solvents includeethers of polyoxypropylene or polyoxyethylene and alphatic alcohol suchas polyoxypropylene 15 stearyl ether and polyoxypropylene glycol 14butyl ether; polyoxypropylene or polyoxyethylene caster oils orhydrogenated caster oils such as polyoxyethylene (3) caster oil andpolyoxyethylene (5) hydrogenated caster oil; polyoxypropylene orpolyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20)sorbitan monooleate and sorbitan trioleate; polyoxypropylene orpolyoxyethylene sorbit fatty acid esters such as polyoxyethylene (6)sorbitol tetraoleate; polyglycerin or glycerin fatty acid esters such asdiglyceryl monooleate, glyceryl dioleate and glyceryl monoisostearate;polyoxypropylene or polyoxyethylene glycerin fatty acid esters such aspolyoxyethylene (5) glyceryl monooleate; polyoxypropylene orpolyoxyethylene alkyl phenyl ethers such as polyoxyethylene (2)nonylphenyl ether and polyoxyethylene (3) octylphenyl ether.

Among the average polarity solvents, either a liquid triglyceride or acosmetically acceptable ester oil is preferred, and eithercapric/caprylic triglyceride or neopentyl glycol dioctoanate is morepreferred. The good penetration effect is not obtained by the averagepolarity solvents per se but is obtained by said liquid crystal.

The amount of the average polarity solvents depend on the amount of thecompounds of formula (I). However, the skin lightening composition ofthe present invention comprises preferably from 5% to 50% of the averagepolarity solvent, more preferably from 10% to 25% of the averagepolarity solvent.

Either one kind or two or more kinds of the average polarity solvent canbe used in the present invention.

Polyhydric Alcohol

Polyhydric alcohols include glycerin, diglycerin, triglycerin,polyglycerin, polypropylene glycol, polyethylene glycol, ethyleneglycol, diethylene glycol, triethylene glycol, propylene glycol,dipropylene glycol, hexylene glycol, 1,3-butylene glycol, 1,4-butyleneglycol, ethylene glycol monoalkyl ether, diethylene glycol monoalkylether, glucose, maltose, sucrose, lactose, xylitose, xylitol, sorbitol,mannitol, maltitol, malbit, panthenol, pentaerythritol, and hyaluronicacid and its salts. Among the polyhydric alcohols, glycerin ispreferred.

The skin lightening composition of the present invention comprisespreferably from 0.1% to 10%, more preferably from 0.5% to 5% of thepolyhydric alcohol.

Either one kind or two or more kinds of the polyhydric alcohol can beused in the present invention.

Solid Fatty Alcohol

Solid fatty alcohols include cetyl alcohol, stearyl alcohol, behenylalcohol, myristyl alcohol, batyl alcohol, cholesterol and phytosterol.Among the solid fatty alcohols, cetyl alcohol is preferred.

The skin lightening composition of the present invention comprisespreferably from 0.1% to 10%, more preferably from 0.5% to 3% of thefatty alcohol.

Either one kind or two or more kinds of the solid fatty alcohol can beused in the present invention.

Nonionic Surfactant

Nonionic surfactants include polyglycerin fatty acid esters, propyleneglycol fatty acid esters, glycerin fatty acid esters, sorbitan fattyacid esters, sugar fatty acid esters, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene sorbit fatty acid esters, polyethyleneglycol fatty acid esters, polyoxyethylene glycerin fatty acid esters,polyoxyethylene castor oils, polyoxyethylene hardened castor oils,polyoxyethylene alkyl ethers, polyoxyethylene phytosterols,polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene lanolins, polyoxyethylene lanolinalcohols, polyoxyethylene beeswax derivatives, polyoxyethylene fattyacid amides, polyether silicone derivatives, and polyoxyethylene fattyacid esters.

The nonionic surfactant could preferably be one which has HLB number of10 to 17 and be solid at room temperature (25° C.). The preferablenonionic surfactants include polyoxyethylene(40) monostearate,polyoxyethylene(21) stearyl ether and decaglyceryl monostearate.

The skin lightening composition of the present invention comprisespreferably from 0.1% to 5%, more preferably from 0.5% to 2% of thenonionic surfactant.

Either one kind or two or more kinds of the nonionic surfactant can beused in the present invention.

Water

The skin lightening composition of the present invention comprisespreferably from 40% to 90%, more preferably from 60% to 80% of water.

Lecithin

Lecithin is a natural product derived from soybean or egg yolk.

The skin lightening composition of the present invention comprisespreferably from 0.5% to 5%, more preferably from 2% to 3% of lecithin.

Combination Actives

A. Sunscreens and Sunblocks

Regulation of skin darkening resulting from exposure to ultravioletlight can be achieved by using combinations of the active skinlightening agents together with sunscreens or sunblocks. Usefulsunblocks include, for example, zinc oxide and titanium dioxide.

Ultraviolet light is a predominant cause of skin darkening. Thus, forpurposes of skin lightening, the combination of a skin lightening agentwith a UVA and/or VB sunscreen is desirable,

A wide variety of conventional sunscreening agents are suitable for usein combination with the skin lightening agent. Segarin, et al., atChapter VIII pages 189 et seq., of Cosmetics Science and Technology,disclose numerous suitable agents. Specific suitable sunscreening agentsinclude, for example: p-aminobenzoic acid, its salts and its derivatives(ethyl, isobutyl, glyceryl esters; p-methylaminobenzoic acid);anthranilates (i.e., o-aminobenzoates; methyl, menthyl, phenyl, benzyl,phenylethyl, linalyl, terpinyl, and cyclohexenyl esters); salicylates(amyl, phenyl, benzyl, menthyl, glyceryl, and dipropyleneglycol esters);Cinnarnic acid derivatives (menthyl and benzyl esters, butyl cinnamoylpyruvate); dihydroxycinnamic acid derivatives (umbelliferone,methylumbelliferone, methylaceto-umbelliferone); trihydroxycinnamic acidderivatives (esculetin, methylesculetin, daphnetin, and the glucosides,esculin and daphnin); hydrocarbons (diphenylbutadiene, stilbene);dibenzalacetone and benzalacetophenone; naphtholsulfonates (sodium saltsof 2-naphthol-3,6-disulfonic and of 2-naphthol-6,8disulfonic acids);dihydroxy-naphthoic acid and its salts; o- andp-Hydroxybiphenyldisulfonates; coumarin derivatives (7-hydroxy,7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole, phenylbenzoxazole, methyl naphthoxazole, various aryl benzothiazoles); quininesalts (bisulfate, sulfate, chloride, oleate, and tannate); quinolinederivatives (8-hydroxyquinoline salts, 2-phenylquinoline); hydroxy- ormethoxy-substituted benzophenones; uric and vilouric acids; tannic acidand its derivatives (e.g., hexaethylether); (butyl carbotol) (6-propylpiperonyl) ether, hydroquinone; benzophenones (oxybenzene,sulisobenzone, dioxybenzone, benzoresorcinol,2,2',4,4'-tetrahydroxybenzophenone,2,2'-dihydroxy4,4'-dimethoxybenzophenone, octabenzone;4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene;and 4-isopropyl-di-benzoylmethane.

Of these, 2-ethylhexyl-p-methoxycinnamate, 4,4'-t-butylmethoxydibenzoyl-methane, 2-hydroxy-4-methoxybenzophenone,octyldimethyl-p-arninobenzoic acid, digalloyltrioleate,2,2-dihydroxy-4-methoxybenzophenone, ethyl-4-(bis(hydroxypropyl))aminobenzoate, 2-ethylhexyl-2-cyano-3,3-diphenylacrylate,2-ethylhexylsalicylate, glyceryl-p-aminobenzoate,3,3,5-trimethylcyclohexylsalicylate, methylanthranilate,p-dimethyl-aminobenzoic acid or aminobenzoate,2-ethylhexyl-p-dimethyl-axino-benzoate, 2-phenylbenzimidazole-5-sulfonicacid, 2-(p-dimethylaminophenyl)-5-sulfonicbenzoxazoic acid and mixturesof these compounds, are preferred.

More preferred sunscreens useful in the compositions useful in thepresent invention are 2-ethylhexyl-p-methoxycinnamate,butylmethoxydibenzoylmethane, 2-hydroxy-4-methoxybenzophenone,octyldimethyl-p-aminobenzoic acid and mixtures thereof.

Also particularly useful in the compositions are sunscreens such asthose disclosed in U.S. Pat. No. 4,937,370 issued to Sabatelli on Jun.26, 1990, and U.S. Pat. No. 4,999,186 issued to Sabatelli & Spirnak onMar. 12, 1991, both of which are incorporated herein by reference. Thesunscreening agents disclosed therein have, in a single molecule, twodistinct chromophore moieties which exhibit different ultra-violetradiation absorption spectra. One of the chromophore moieties absorbspredominantly in the UVB radiation range and the other absorbs stronglyin the UVA radiation range.

Preferred members of this class of sunscreening agents are4-N,N-(2-ethylhexyl)methylaminobenzoic acid ester of2,4-dihydroxybenzophenone; N,N-di-(2-ethylhexyl)-4-aminobenzoic acidester with 4-hydroxydibenzoylmethane;4-N,N-(2-ethylhexyl)methylaminobenzoic acid ester with4-hydroxydibenzoylmethane; 4-N,N-(2-thylhexyl)methylaminobenzoic acidester of 2-hydroxy-4-(2-hydroxy-ethoxy)benzophenone;4-N,N-(2-ethylhexyl)-methylaminobenzoic acid ester of4-(2-hydroxyethoxy)dibenzoylmethane N,N-di-(2-ethylhexyl)-4-aminobenzoicacid ester of 2-hydroxy-4-(2-hydroxyethoxy)benzophenone; andN,N-di-(2-ethylhexyl)-4-aminobenzoic acid ester of4-(2-hydroxyethoxy)dibenzoylmethane and mixtures thereof.

A safe and effective amount of sunscreen may be used in the compositionsuseful in the present invention. The sunscreening agent must becompatible with the skin lightening agent. The composition preferablycomprises from about 1% to about 20%, more preferably from about 2% toabout 10%, of a sunscreening agent. Exact amounts will vary dependingupon the sunscreen chosen and the desired Sun Protection Factor (SPF).

An agent may also be added to any of the compositions useful in thepresent invention to improve the skin substantivity of thosecompositions, particularly to enhance their resistance to being washedoff by water, or rubbed off. A preferred agent which will provide thisbenefit is a copolymer of ethylene and acrylic acid. Compositionscomprising this copolymer are disclosed in U.S. Pat. No. 4,663,157,Brock, issued May 5, 1987, which is incorporated herein by reference.

B. Anti-Inflammatory Agents

In a preferred skin lightening composition useful in the presentinvention, an anti-inflammatory agent is included as an active alongwith the skin lightening agent. The inclusion of an anti-inflammatoryagent enhances the skin lightening benefits of the compositions. Theanti-inflammatory agent protects strongly in the UVA radiation range(though it also provides some UVB protection as well). The topical useof anti-inflammtory agents reduces darkening of the skin resulting fromchronic exposure to UV radiation. (See U.S. Pat. No. 4,847,071, Bissett,Bush, and Chatterjee, issued Jul. 11, 1989, incorporated herein byreference; and U.S. Pat. No. 4,847,069, Bissett and Chatterjee, issuedJul. 11, 1989, incorporated herein by reference.)

A safe and effective amount of an anti-inflammatory agent may be addedto the compositions useful in the present invention, preferably fromabout 0.1% to about 10%, more preferably from about 0.5% to about 5%, ofthe composition. The exact amount of anti-inflammatory agent to be usedin the compositions will depend on the particular anti-inflammatoryagent utilized since such agents vary widely in potency.

Steroidal anti-inflammatory agents, including but not limited to,corticosteroids such as bydrocortisone, hydroxyltriamcinolone,alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethsonedipropionate, clobetasol valemate, desonide, desoxymethasone,desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diflucortolone valerate, fluadrenolone, flucloroloneacetonide, fludrocortisone, flumethasone pivalate, fluosinoloneacetonide, fluocinonide, flucortine butylester, fluocortolone,fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide,hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone,triamcinolone acetonide, cortisone, cortodoxone, flucetonide,fludrocortisone, difluorosone diacetate, fluradrenolone acetonide,medrysone, amcinafel, amcinafide, betamethasone and the balance of itsesters, chloroprednisone, chlorprednisone acetate, clocortelone,clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide,fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate,hydrocortisone cyclopentylpropionate, hydrocortmate, mepreddisone,paramethasone, prednisolone, prednisone, beclomethasone dipropionate,triamcinolone, and mixtures thereof may be used. The preferred steroidalanti-inflammatory for use is hydrocortisone.

A second class of anti-inflammatory agents which is useful in thecompositions includes the non-steroidal anti-inflammatory agents. Thevariety of compounds encompassed by this group are well-known to thoseskilled in the art For detailed disclosure of the chemical structure,synthesis, side effects, etc., of non-steroidal anti-inflammatoryagents, reference may be had to standard texts, includingAnti-inflammatory and Anti-Rheumatic Drugs, K. D. Rainsford, Vol. I-III,CRC Press, Boca Raton, (1985), and Anti-inflammatory Agents, Chemistryand Pharmacology, 1, R. A. Scherrer, et al., Academic Press, New York(1974).

Specific non-steroidal anti-inflammatory agents useful in thecomposition invention include, but are not limited to:

1) the oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, andCP-14,304;

2) the salicylates, such as aspirin, disalcid, benorylate, trilisate,safapryn, solprin, diflunisal, and fendosal;

3) the acetic acid derivatives, such as diclofenac, fenclofenac,indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,zidometacin, aceinatacin, fentiazac, zomepiract, clidanac, oxepinac, andfelbinac;

4) the fenamates, such as mefenarnic, meclofenamic, flufenamic,niflumic, and tolfenamic acids;

5) the propionic acid derivatives, such as ibuprofen, naproxen,benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and

6) the pyrazoles, such as phenybutazone, oxyphenbutazone, feprazone,azapropazone, and trimethazone.

Mixtures of these non-steroidal anti-inflarnmatory agents may also beemployed, as well as the pharmaceutically-acceptable salts and esters ofthese agents. For example, etofenamate, a flufenamic acid derivative, isparticularly useful for topical application. Of the nonsteroidalanti-inflammatory agents, ibuprofen, naproxen, flufenamic acid,mefenamic acid, meclofenamic acid, piroxicam and felbinac are preferred;ibuprofen, naproxen, and flufenamic acid are most preferred.

Another class of anti-inflammatory agents which are useful in thecompositions are the anti-inflammatory agents disclosed in U.S. Pat. No.4,708,966, Loomans et al., issued Nov. 24, 1987. This patent discloses aclass of nonsteroidal anti-inflammatory compounds which comprisespecifically substituted phenyl compounds, especially substituted2,6-di- tert-butyl phenol derivatives. For example, compounds selectedfrom 4-(4'-pentyn-3'-one)-2,6-di-t-butylphenol;4-(5'-hexynoyl)-2,6-di-t-butylphenol;4-((S)-(-)-3'-methyl-5'-hexynoyl)-2,6-di-t-butylphenol;4-((R)-(+)-3'-methyl-5'-hexynoyl)-2,6-di-t-butylphenol; and4-3',3'-dimethoxypropionyl)-2,6-di-t-butylphenol are useful in methodsof the present invention; 4-(5'-hexynoyl)-2,6-d-t-butylphenol is mostpreferred.

Yet another class of anti-inflammatory agents which are useful in thecompositions are those disclosed in U.S. Pat. No. 4,912,248, Mueller,issued Mar. 27, 1990. This patent discloses compounds and diastereomericmixtures of specific 2-naphtlilyl-containing ester compounds, especiallynaproxen ester and naproxol ester compounds, having two or more chiralcenters. For example, compounds selected from (S)-naproxen-(S)-2-butylester, (S)-naproxen-(R)-2-butylester, (S)-naproxol-(R)-2-methylbutyrate, (S)-naproxol-(S)-2-methyl butyrate, diasteromeric mixtures of(S)-naproxen-(S)-2-butyl ester and (S)-naproxen-(R)-2-butyl ester, anddiasteromeric mixtures of (S)-naproxol-(R)-2-methyl butyrate and(S)-naproxol-(S)-2-methyl butyrate are useful in the present invention.

Finally, so-called "natural" anti-inflammatory agents are useful inmethods of the present invention. For example, candelilla wax, alphabisabolol, aloe vera, Manjistha (extracted from plants in the genusRubia, particularly Rubia Cordifolia), and Guggal (extracted from plantsin the genus Commiphora, particularly Commiphora Mukul), may be used.

Another preferred composition useful in the present invention comprisesa skin lightening agent, a sunscreen, and an anti-inflammatory agenttogether for skin lightening in the amounts disclosed for eachindividually hereinabove.

C. Anti-Oxidants/Radical Scavengers

In a preferred skin lightening composition useful in the presentinvention, an anti-oxidant/radical scavenger is included as an activealong with the skin lightening agent. The inclusion of ananti-oxidant/radical scavenger increases the skin lightening benefits ofthe composition.

A safe and effective amount of an anti-oxidant/radical scavenger may beadded to the compositions useful in the present invention, preferablyfrom about 0.1% to about 10%, more preferably from about 1% to about 5%,of the composition.

Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) andits salts, tocopherol (vitamin E), tocopherol sorbate, other esters oftocopherol, butylated hydroxy benzoic acids and their salts,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commerciallyavailable under the tradename Trolox□), gallic acid and its alkylesters, especially propyl gallate, uric acid and its salts and alkylesters, sorbic acid and its salts, the ascorbyl esters of fatty acids,amines (e.g., N,N-diethylhydroxylamine, amino-guanidine), sulfhydrylcompounds (e.g., glutathione), and dihydroxy fumaric acid and its saltsmay be used.

In a preferred composition useful in the present invention, compositionscomprise one, any two, or all three of a sunscreening agent,anti-inflammatory agent, and/or an anti-oxidant/radical scavenging agentincluded as actives along with the skin lightening agent. The inclusionof two or all three of these agents with the skin lightening agentincreases the skin lightening benefits of the composition.

D. Chelators

In a preferred composition useful in the present invention, a chelatingagent is included as an active along with the skin lightening agent. Asused herein, "chelating agent" means an active agent capable of removinga metal ion from a system by forming a complex so that the metal ioncannot readily participate in or catalyze chemical reactions. Theinclusion of a chelating agent increases the skin lightening benefits ofthe composition.

A safe and effective amount of a chelating agent may be added to thecompositions useful in the present invention, preferably from about 0.1%to about 10%, more preferably from about 1% to about 5%, of thecomposition. Chelators useful in compositions are disclosed in U.S.patent application Ser. No. 619,805, Bissett, Bush & Chatterjee, filedNov. 27, 1990 (which is a continuation of U.S. patent application Ser.No. 251,910, filed Oct. 4, 1988), U.S. patent application Ser. No.514,892, Bush & Bissett, filed Apr. 26, 1990; and U.S. patentapplication Ser. No. 657,847, Bush, Bissett & Chatterjee, filed Feb. 25,1991; all incorporated herein by reference. Preferred chelators usefulin compositions of the present invention are furildioxime andderivatives thereof In a preferred composition useful in the presentinvention, compositions comprise one, any two, any three, or all four ofa sunscreening agent, anti-inflammatory agent, anti-oxidant/radicalscavenging agent, and/or chelating agent included as actives along withthe skin lightening agent. The inclusion of two, three, or all four ofthese agents with the skin lightening agent increases the skinlightening benefits of the composition.

E. Retinoids

In a preferred composition useful in the present invention, a retinoid,preferably retinoic acid, is included as an active along with the skinlightening agent. The inclusion of a retinoid increases the skinlightening benefits of the composition. A safe and effective amount of aretinoid may be added to the compositions useful in the presentinvention, preferably from about 0.001% to about 2%, more preferablyfrom about 0.01% to about 1% of the composition. As used herein,"retinoid" includes all natural and/or synthetic analogs of Vitamin A orretinol-like compounds which possess the biological activity of VitaminA in the skin as well as the geometric isomers and stereo isomers ofthese compounds, such as all-trans retinoic acid and 13-cis-retinoicacid.

In a preferred composition useful in the present invention, compositionscomprise one, any two, any three, any four, and/or all five of asunscreening agent, anti-inflammatory agent, anti-oxidantradicalscavenging agent, chelating agent, and/or a retinoid included as activesalong with the skin lightening agent. The inclusion of two, three, four,or all five of these agents with the skin lightening agent increases theskin lightening benefits of the composition.

Other Optional Components

Other optional components include thickeners such as carboxy vinylpolymer, preservatives, liquid and paste pigments, astringents, pHbuffers, perfumes, infrared screening agents, amphoteric and solidamorphous lipids, vitamins, nutrients, and skin conditioning agents.

Useful skin conditioning agents are beta-glycyrrhetic acid and itsderivatives, vegetation extracts, alantoin, collagen, and extract andtreated elastin fibers.

The topical compositions useful in the present invention may be madeinto emulsion type product. These include, but are not limited to, milkylotions, creams and ointments.

The emulsion type product comprises a liquid crystal comprising thecompound of formula (I), an average polarity solvent, a polyhydricalcohol, a fatty alcohol, a nonionic surfactant, water and lecithin.

Emulsions according to the present invention generally contain acosmetically acceptable aqueous or organic solvent such as ethanol,isopropanol, sorbitol esters, and mixtures thereof and a lipid or oil.Lipids and oils may be derived from animals, plants, or petroleum andmay be natural or synthetic (i.e., man-made).

The emulsion may also contain an anti-foaming agent to minimize foamingupon application to the skin. Anti-foaming agents include high molecularweight silicones and other materials well known in the art for such use.

The emulsions preferably comprise a silicone for imparting a preferredskin feel. Generally such silicones have a low molecular weight.Suitable such silicones include cyclomethicones, dimethicones, andblends such as Dow Corning 200 fluid (especially 10 cs) and Dow CorningQ2-1401. Such silicones are commercially available from the Dow CorningCorp. of Midland, Mich.

The skin lightening composition of the present invention may comprise atopical cosmetically acceptable emollient. As used herein, "emollient"refers to a material used for the prevention or relief of dryness, aswell as for the protection of the skin. A wide variety of suitableemollients are known and may be used herein. Sagarin, Cosmetics, Scienceand Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972), incorporatedherein by reference, contains numerous examples of materials suitable asan emollient. The skin lightening cosmetic of the present inventiontypically comprises from about 5% to about 50%, preferably from about10% to about 25%, of emollient.

Methods for Lightening Skin in Mammals

The present invention also relates to methods for skin lightening inmammals comprising topical application of the skin lighteningcomposition of the present invention. The amount of active agent andfrequency of application will vary widely depending upon the skin coloralready in existence in the subject, the rate of further darkening ofthe skin, and the level of lightening desired.

A safe and effective amount of skin lightening agent in a topicalcomposition is applied, generally from about 1 g to about 10 g per cm²skin per application, preferably from about 2 g to about 8 g/cm² skinper application, more preferably from about 3 g to about 7 g/cm² skin,also preferably from about 4 g to about 5 g/cm² skin. Applicationpreferably ranges from about four times a day to about twice a week,more preferably from about three times a day to about once every otherday, more preferably still from about once daily to about twice daily.Application for at least five days is required to see a skin lighteningeffect in lower animals. Application for at least one month is requiredto see an effect in humans. After lightening is achieved, the frequencyand dosage can be reduced to a maintenance level, as desired. Suchmaintenance varies according to the individual, but is preferably fromabout 1/10 to about 1/2, more preferably from about 1/5 to about 1/3 ofthe original dosage and/or frequency, as needed.

A preferred method of the present invention for skin lightening inmammals involves applying the skin lightening composition of the presentinvention further comprising a safe and effective amount of one or moreof a sunscreening agent, an anti-inflammatory agent, ananti-oxidant/radical scavenging agent, a chelating agent and/or aretinoid. The amount of sunscreening agent applied is preferably fromabout 0.01 mg to about 0.1 mg per cm² skin. The amount ofanti-inflammatory agent applied is preferably from about 0.005 mg toabout 0.5 mg, more preferably from about 0.01 mg to about 0.1 mg per cm²skin. The amount of antioxidant/radical scavenging agent preferablyapplied is from about 0.01 mg to about 1.0 mg, more preferably fromabout 0.05 mg to about 0.5 mg per cm² skin. The amount of chelatingagent preferably applied is from about 0.001 mg to about 1.0 mg, morepreferably from about 0.01 mg to about 0.5 mg, still more preferablyfrom about 0.05 mg to about 0.1 mg per cm² skin. The amount of retinoidapplied is preferably from about 0.001 mg to about 0.5 mg per cm² skin,more preferably from about 0.005 mg to about 0.1 mg per cm² skin. Theamount of skin lightening agent applied is preferably from about 0.001mg to about 2 mg per cm² skin per application, more preferably fromabout 0.01 mg to about 1 mg per cm² skin per application.

Procedure for Making a Skin Lightening Composition of the PresentInvention

For example, a skin lightening composition of the present inventionwhich comprises a liquid crystal can be made by the steps of

(i) mixing a safe and effective amount of a compound of the formula (I),an average polarity solvent, a fatty alcohol, a nonionic surfactant andlecithin at the temperature of 60° C. to 100° C. to obtain mixture 1,and

(ii) mixing a polyhydric alcohol and water with the mixture 1 whilemaintained at the temperature of 45° C. to 100° C.

The mixture obtained by the above steps (i) and (ii) is usually cooledto room temperature.

The other component can be mixed according to the convention manner,however, generally oil-soluble components can be added in the above step(i) and water-soluble components can be added in the above step (ii).

The liquid crystal can be detected by observing the shape of the liquidcrystal by a polarization microscope.

EXAMPLES

The following examples further describe and demonstrate embodimentswithin the scope of the present invention. The examples are given solelyfor the purpose of illustration and are not to be construed aslimitations of the present invention, as many variations thereof arepossible without departing from the spirit and scope of the invention.

Test Example 1

Procedure for Making Control Composition

THPOP is dissolved in polypropylene glycol (14) butyl ether (THPOPphase-1) Separately, polyoxyethylene (21) stearyl alcohol,polyoxyethylene (2) stearyl alcohol, cetyl alcohol, stearyl alcohol,cyclomethicone and ascorbyl palmitate are dissolved at 70° C. andstirred well. The THPOP phase-1 is added thereto and mixed continuously.(THPOP phase-2)

In another vessel, all other ingredients than the above are dissolved at70° C. (water phase)

The THPOP phase-2 and the water phase are mixed well and allowed to coolto obtain oil-in-water emulsion (o/w emulsion). The components ofcontrol is shown in Table 1.

Procedure for Making Test Composition No. 1

THPOP, caprylicicapric triglyceride (Migyol 812), cetyl alcohol,polyoxyethylene(40) monostearate and lecithin are mixed together andheated to 70° C. Then, deionized water and glycerin are added theretowith stirring and the mixture is emulsified. Then the emulsified mixtureis cooled to room temperature with stirring to obtain an emulsion with aliquid crystal. The emulsion with the liquid crystal and all otheringredients than the above are mixed together to obtain CompositionNo. 1. The component of composition No. 1 is shown in Table 2.

Procedure for Making Test Composition No. 2

THPOP, neopentyl glycol dioctoanate (Cosmol 525), cetyl alcohol,polyoxyethylene(40) monostearate and lecithin are mixed together andheated to 70° C. Then, deionized water and glycerin are added theretowith stirring and the mixture is emulsified. Then the emulsified mixtureis cooled to room temperature with stirring to obtain an emulsion with aliquid crystal. The emulsion with the liquid crystal and all otheringredients than the above are mixed together to obtain Composition No.2. The component of composition No. 2 is shown in Table 3.

                  TABLE 1                                                         ______________________________________                                        Control (Oil in Water emulsion)                                               Component             Amount (weight %)                                       ______________________________________                                        De-ionized water      75.70                                                   Hydrochloric Acid 1N  2.30                                                    Triethanolamine       1.40                                                    Mg Ascorbic Phosphate 0.10                                                    Sodium Metabisulfite  0.05                                                    Disodium EDTA         0.05                                                    Polyoxyethylene (21) stearyl alcohol (21)                                                           2.00                                                    Polyoxyethylene (2) stearyl alcohol (2)                                                             1.00                                                    Polypropylene glycol (14) Butyl Ether                                                               7.50                                                    Cetyl Alcohol         3.00                                                    Stearyl Alcohol       1.50                                                    Cyclomethicone        1.00                                                    Ascorbyl Palmitate    0.10                                                    THPOP                 3.00                                                    Butylene glycol       1.00                                                    Glydant Plus          0.30                                                    ______________________________________                                         ("Glydant Plus" is Dimethylol5,5- dimethylhydantoin (and) Iodopropynyl        Butyl carbamate)                                                         

                  TABLE 2                                                         ______________________________________                                        Composition No. 1                                                             Component            Amount (weight %)                                        ______________________________________                                        Lecithin             3.00                                                     Polyoxyethylene(40) monostearate                                                                   1.00                                                     (Myrj 52)                                                                     Cetyl Alcohol        1.00                                                     Caprylic/Capric Triglyceride                                                                       15.00                                                    (Migyol 812)                                                                  D-delta Tocopherol   0.10                                                     Glycerin             5.00                                                     Propylparaben        0.10                                                     Methylparaben        0.20                                                     THPOP                3.00                                                     De-ionized Water     69.13                                                    Sodium Metabisulfite 0.08                                                     Sodium Sulfite       0.20                                                     Sodium Hydroxide     0.59                                                     Carboxy vinyl polymer (Carbopol 980)                                                               1.00                                                     Benzyl Alcohol       0.60                                                     ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Composition No. 2                                                             Component            Amount (weight %)                                        ______________________________________                                        Lecithin             3.00                                                     Polyoxyethylene(40) monostearate                                                                   1.00                                                     (Myrj 52)                                                                     Cetyl Alcohol        1.00                                                     Neopentyl glycol dioctoanate                                                                       21.00                                                    (Cosmol 525)                                                                  D-delta Tocopherol   0.10                                                     Glycerin             5.00                                                     Propylparaben        0.10                                                     Methylparaben        0.20                                                     THPOP                3.00                                                     De-ionized Water     63.13                                                    Sodium Metabisulfite 0.08                                                     Sodium Sulfite       0.20                                                     Sodium Hydroxide     0.59                                                     Carboxy vinyl polymer (Carbopol 980)                                                               1.00                                                     Benzyl Alcohol       0.60                                                     ______________________________________                                    

Test Method

(1) Apparatus

The unjacketed diffusion cell is used. The cross-sectional area forpenetration is 0.79 cm². This design is described by E. W. Merritt andE. R. Cooper, J. Controlled Release, 1(2), 161-162. Low glass tops thatpermit evaporation of the dose solution will be used for this study.

The diffusion cells are maintained at body temperature of 37° C. inaluminum blocks which sit in a stirring-heating module (Peirce ChemicalCo.). Each aluminum block can accommodate six cells. The module controlsthe temperature and provides the stirring motor for the diffusion cells.

(2) Buffer Solution

The physiological saline solution used in this preparation is Dulbeco'sphosphate buffered saline without calcium chloride and sodiumbicarbonate (hereafter called "pbs") obtained from Wako Pure ChemicalIndustries LTD, CAM7276. Pbs is reconstituted with distilled wateraccording to labeled instruction and 0.002% (s/v) sodium azide (WakoPure Chemical Industries LTD, KCE 6293) is added to retard microbialgrowth. The pbs solution is maintained in a 37° C. water bath throughoutthe experiment in order to degas the solution. Evacuation of thesolution using an aspirator, with stirring, for 15 minutes is alsoacceptable.

(3) Excised Human Cadaver Skin

Frozen excised human skin to a thickness of 0.25 mm (following washingand hair clipping) can be obtained from the Ohio Valley Skin and TissueCenter (Shriners Burns Institute, Cincinnati, Ohio). Skin is bathed in asolution of broad-spectrum antibiotics for 24 hours, treated with a 10%glycerol solution, wrapped in gauze, and placed in sealed sterile foilpacks. The skin is cut into ˜1.2×1.2 cm² using a scalpel (Keisei Medicalindustrial Co., handle #4, balde #21). The receptor compartments of theglass diffusion cells, filled with pbs solution (4-5 ml), are maintainedat 37° C. in the aluminum blocks. The squares are mounted horizontallyonto the cells with the stratum corneum facing the donor compartment andthe dermis in contact with the receptor compartment. Non-occluded glasstops are placed onto the cells and firmly clamped in place. The aluminumblocks are placed back into the modules and micro magnetic stir bars areput into the receptor compartments of the cells to continually stirthroughout the course of the experiment.

(4) Experimental Methods

The skin is allowed to equilibrate overnight, or for a minimum of 16hours, with the dermis in contact with pbs solution and the stratumcorneum exposed to air. A basic computer program is used to randomizethe treatment groups and each diffusion cell is labeled accordingly.Following equilibration and just prior to dosing, the solution in thereceptor compartment is discarded and refilled with fresh pbs solution.This procedure consists of pouring out the solution in the receptorcompartment, rinsing with 2-3 ml of fresh pbs solution and refillingwith fresh pbs solution. When pouring out solution, a gloved handcontaining a magnet is used to prevent the micro stir bar from beingexpelled. Air bubbles which collect on the dermal surface of the skinare removed by holding the glass cell at an angle and gently tapping.Temperature of the solution in the receptor compartment is randomlyobserved, and adjusted if necessary, throughout the course of theexperiment using a SATO PAC-9400 thermocouple thermometer.

(5) Dosing and Sampling Procedures

Test compositions and controls are dosed onto the stratum corneum (donorcompartment) using a pipettor. If a small volume of material is dosed,the pipette tip is used to distribute the material evenly over the skin.If occlusion is called for, a small piece of parafilm is placed over theglass top immediately following dosing. Receptor compartment samples areusually collected 6 and 24 hours post-dose. Sampling consists of pouringthe solution from the receptor comparment into a vial, risining with 2-3ml of pbs solution and adding this rinse to the vial, then refillingwith fresh pbs solution. Blank samples (pbs solution only) are obtainedafter each collection period and used for the background determination.Dummy dosing solution aliquots are weighed into scintillation vials forHPLC analysis in order to calculate the average dose applied to eachcell. Aliquots from a prepared solution of test material and ethanol arealso submitted for HPLC analysis to standardize the results andestablish a conversion factor for the data analysis.

(6) Cleaning Procedures

At the end of the experiment, cells are dismantled and washed in astrong detergent solution (Alconox), rinsed with distilled water andallowed to air dry. Skin is wrapped in foil and stored in the freezerprior to disposal by incineration. In case of lacking incinerationfacility, a concentrated H₂ SO₄ bath can be used to dissolve skin. Stirbars are rinsed and placed overnight in a beaker containing ethanol.Clamps are rinsed in distilled water and occasionally washed in anAlconox solution.

(7) HPLC Analysis

The penetration samples and aliquots of dosing and standard solutionsare then analyzed for THPOP% by HPLC, (High Performance LiquidChromatography-Shimazu LC-9A using JSPHERE ODS M80 Column)

Penetration value was calculated by the following equation.

    Penetration value(%)=penetrated amount of THPOP at each time point(mg)×100 amount of THPOP in applied composition(mg)

The test result is shown in Table 4.

                  TABLE 4                                                         ______________________________________                                                    Penetration value (%) in each time                                Tested composition                                                                          6 hrs      24 hrs                                               ______________________________________                                        Composition No. 1                                                                           5.20       18.07                                                Composition No. 2                                                                           6.47       23.92                                                Control       2.94       6.54                                                 ______________________________________                                    

As shown in the above Table 4, excellent penetration enhancing effectcan be obtained by the composition No. 1 and the composition No. 2 ofthe present invention.

What is claimed is:
 1. A skin lightening composition comprising(a) asafe and effective amount of a compound of the formula (I) ##STR4##wherein Z is Oxygen or Sulfur, (b) an average polarity solvent (c) apolyhydric alcohol (d) a solid fatty alcohol (e) a nonionic surfactant(f) water, and (g) lecithinwherein at least a portion of the abovecomponents (a), (b), (c), (d), (e), (f) and (g) forms a liquid crystal.2. A skin lightening composition comprising by weight to the entirecomposition(a) 0.001-10% of a compound of the formula (I) ##STR5##wherein Z is Oxygen or Sulfur, (b) 5-50% of an average polarity solvent(c) 0.1-10% of a polyhydric alcohol (d) 0.1-10% of a solid fatty alcohol(e) 0.1-5% of a nonionic surfactant (f) 40-90% of water, and (g) 0.5-5%of lecithinwherein at least a portion of the above components (a), (b),(c), (d), (e), (f) and (g) forms a liquid crystal.
 3. The composition ofclaim 2 wherein Z is Oxygen.
 4. The composition of claim 2 wherein Z isSulfur.
 5. The composition of claim 2 wherein the compound of theformula (I) is dissolved in the average polarity solvent.
 6. Thecomposition of claim 2 wherein the average polarity solvent has theratio of Organicity and Inorganicity of 0.2 to 3.6.
 7. The compositionof claim 2 wherein the average polarity solvent is a liquidtriglyceride.
 8. The composition of claim 2 wherein the average polaritysolvent is a cosmetically acceptable ester oil.
 9. The composition ofclaim 2 wherein the average polarity solvent is capric/caprylictriglyceride.
 10. The composition of claim 2 wherein the averagepolarity solvent is neopentyl glycol dioctoanate.
 11. The composition ofclaim 2 wherein the polyhydric alcohol is glycerin.
 12. The compositionof claim 2 wherein the solid fatty alcohol is cetyl alcohol.
 13. Thecomposition of claim 2 wherein the nonionic surfactant has HLB of 2 to20.
 14. The composition of claim 2 wherein the nonionic surfactant ispolyoxyethylene(40) monosteamate.
 15. The composition of claim 2 whereinthe composition is a topical composition.
 16. An emulsion compositionwhich comprises said liquid crystal according to claim
 2. 17. A creamcomposition which comprises said liquid crystal according to claim 2.18. A method for skin lightening in mammals which comprises topicalapplication of skin lightening composition according to claim
 1. 19. Aprocess for preparing a skin lightening composition comprising a liquidcrystal which comprises the steps of(i) mixing by weight to the entirecomposition(a) 0.001-10% of a compound of the formula (I) ##STR6##wherein Z is Oxygen or Sulfur, (b) 5-50% of an average polarity solvent(c) 0.1-10% of a solid fatty alcohol (d) 0.1-5% of a nonionicsurfactant, and (e) 0.5-5% of lecithin at the temperature of 60° C. to100° C. to obtain mixture 1, and (ii) mixing with the mixture 1 byweight to the entire composition(f) 0.1-10% of a polyhydric alcohol, and(g) 40-90% of waterwhile maintained at the temperature of 45° C. to 100°C.